Pain generated by peripheral tissue injury leads to the activation of populations of small primary afferents (C fibers), populations of which release substance P (e.g. are peptidergic) and activate second order spinal dorsal horn neurons. This peptide acts on the second order neuron through neurokinin 1 (NK-1) receptors to excite the second order neurons. While other transmitters (such as glutamate) released from the afferent, may play a more important role in exciting the second neurons, the NK1 receptor can be considered to mark the cells, many of which project to the brain, which are playing an important role in pain processing.
It is known that regulating the excitability of the small afferent second order link can produce a powerful and selective analgesia. One example of this is the powerful analgesic action of morphine when given spinally. Because mu opiate receptors (though which morphine acts in spinal cord) are located on many of these peptidergic C fibers, and because the activation of the terminal opiate receptors blocks the opening of voltage sensitive calcium channels, this presynaptic effect serves to block transmitter release from only these C fiber terminals. As these opiate receptors are located only on small afferents, the release of transmitters from other sensory axons, which are often non nociceptive (e.g. mediates for example light touch), are not affected. Spinal opiates affect pain, but not non-painful sensation. In addition, it is known that there are opiate receptors which are on second order neurons and the activation of these neurons by noxious input can be reduced by the agonist occupancy of these post synaptic opiate receptors.
The above commentary emphasizes the role of the NK1 receptor as marking cells which are post synaptic to pain fibers on mu opioid receptors present on spinal C fiber (pain fiber) terminals, and on second order neurons which are carrying pain information. This organization is illustrated in FIG. 1.
An important property of these NK1 and mu opioid receptors is that they are G protein coupled receptors. When their respective agonists occupy them they will internalize the bound agonists into the cell.
It has been shown that this internalization process can be used to target specific cell to take up large proteins. One well-known example is the saporin complex. Coupling this 31 kDa toxin to sP will cause that toxin to be taken up into neurons, which are expressing NK1 receptors. Upon binding, this complex internalizes into the cell (and only that cell with an NK1 receptor), where upon the toxin will kill that cell. Studies with the intrathecal delivery of substance P-Saporin have shown a prominent analgesia after such treatment reflecting the importance of these important NK1 bearing neurons in pain processing. This strategy is by its nature results in permanent and irreversible neuron loss. Such therapy would be limited to those patients with terminals illnesses. Therefore, there is a critical need to develop a new therapy that can be applicable to the vast majority of pain patients suffering from chronic pains, such as, for example, musculoskeletal and low back pain.